Is VPS28 p.Pro18Leu (c.53C>T) pathogenic?

VPS28 p.Pro18Leu (c.53C>T) is classified Uncertain significance in VPS28 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-26). AlphaMissense: ambiguous (0.4773); Ultra-rare (popmax 0.0165%, mid).

How common is VPS28 p.Pro18Leu (c.53C>T) in the general population?

VPS28 p.Pro18Leu (c.53C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about VPS28 p.Pro18Leu (c.53C>T)?

AlphaMissense predicts ambiguous (score 0.4773) — an in-silico prediction, not a clinical call.

VPS28 p.Pro18Leu

c.53C>T · rs782779027 · VCV2509902

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4773 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
AlphaMissense	0.4773	ambiguous
REVEL	0.336	indeterminate
SaProt	LLR -10.95	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,208 bp · p 0.071 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 0.00037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000685% 11/1,605,910 alleles · ultra-rare exomes 10/1,453,802 · genomes 1/152,108 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
South Asian	0.00223%	44,923
Admixed American	0.0017%	58,934
Remaining individualsnot grpmax-eligible	0.00161%	62,104
European (non-Finnish)	0.00051%	196,107

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VPS28
Protein: p.Pro18Leu
Coding: c.53C>T
MANE Select: NM_016208
dbSNP: rs782779027
Type: single nucleotide variant
Location: chr8:144426193 (GRCh38)
Gene constraint: LOEUF 1.476 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.18 · 1 PDB
Residue 18: the vps28 n-terminal domain

Full VPS28 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

VPS28 c.548+57G>C Uncertain significance ★ same type
VPS28 c.548+9C>T Uncertain significance ★ same type
VPS28 c.549-21T>C Uncertain significance ★ same type
VPS28 c.549-23C>T Uncertain significance ★ same type
VPS28 c.549-51G>A Uncertain significance ★ same type
VPS28 c.549-5C>T Uncertain significance ★ same type
VPS28 c.549-9C>T Uncertain significance ★ same type
VPS28 p.Ala51Asp Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vps28-p-pro18leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown